Neuroinflammation is a convergent feature of neurodegenerative diseases, hemorrhagic and ischemic stroke, and spinal cord injury. Central to this process is the Toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) signaling axis, which senses damage-associated molecular patterns to initiate innate immune responses. While the canonical inflammatory role of TLR4 is well-defined, recent evidence identifies it as a critical regulator of non-canonical cell death-including pyroptosis and necroptosis-and a requisite priming signal for NLRP3 inflammasome activation. This review examines the expanding complexity of TLR4/MyD88 signaling, moving beyond local central nervous system (CNS) activation to its regulation via the microbiota-gut-brain axis, metabolic endotoxemia, and epigenetic modifications such as miRNA and lncRNA networks. We synthesize these molecular insights within the context of specific pathologies, particularly Alzheimer’s disease, Parkinson’s disease, and traumatic CNS injury. Finally, we evaluate the translational potential of targeting this axis, highlighting the shift from broad-spectrum anti-inflammatories to precision strategies involving nanodelivery systems and immunometabolic modulation.

Funding: The authors’ research on cerebrovascular diseases was supported by grants from Henan Province Medical Science and Technology Research Program (SBGJ202403031); Postdoctoral Fellowship Program of China Postdoctoral Science Foundation (GZC20232401); Hunan Provincial Natural Science Foundation (2023JJ40572); National Natural Science Foundation of China (U25A2065, W2541024); Key Advantageous Discipline Construction Project of Guizhou Provincial Health Commission (2023, Emergency Department); Guizhou Provincial Natural Science Foundation (Qiankehe Foundation MS[2025]432); National Natural Science Foundation of China (NSFC) Regional Fund Cultivation Program Project of the Affiliated Hospital of Guizhou Medical University (gyfynsfc[2023]-47).